Protein methylation study by click chemistry

Bioorthogonal Profiling of Protein Methylation Using Azido Derivative of S-Adenosyl-L-methionine, Minkui Luo, et al, J. Am. Chem. Soc. 2012, 134, 5909-5915
dx.doi.org/10.1021/ja2118333

A few key points:
1. Protein methytransferase transfers methyl group from  S-Adenosyl-L-methionine (SAM) to specific proteins.
2. Selective mutation of a transferase allows its acceptance of modified azido-SAM. 
3. Instead of methyl group, the azido-R group was transferred to specific proteins in cells with above SAM transferase.
4. Copper-free Click chemistry and MS reveal the identity of the specific methylated protein.
5. Therfore, methyltransferase - target protein link is established.  

Antibody-type compounds by iterative in situ click chemistry

Angew. Chem. Int. Ed. 2009, 48, (27) 4944

The work by Heath, Fokin, Sharpless et al is summarized in the above graph. To make a few points:
1. For protein binding, Phage-display peptide aptamers are not as popular as DNA aptamers
2. OBOC (one-bead-one-compound) allows for identity tracking in combinatorial chemistry and ligand selection 
3. Multi-valency or multi-dentate ligands provide superior and amazing binding power than the individual components. Remember EDTA? 
4. Protein binding agents, particularly surface binding ones, almost certainly adopt multiple interactions with the target protein, offering superior binding affinity and / or specificity.
5. Triazole linkage in a peptide may present itself much like an amino acid, in terms of size and hydrogen bonding capacity.
6. The above strategy quickly selected nM affinity in third round, from 500uM in first round. 
7. This iterative strategy effectively "expanded" the size of the library (~0.1 million sequences)
8. In situ click chemistry is guided by the surface binding, pulling alkyne and azide into position for reaction for the realization of fragment-based assembly of high-affinity protein binders.
9. The resulting ligands are water-soluble and stable chemically, biochemically, and thermally.
10. Gram-scale synthesis of the selected sequence is straight-forward using CuAAC. 
11. The binding is off-site (non-active site binding), on surface, and highly selective, the general feature of natural antibody.